The genetic basis of neuroticism

Gray has drawn upon genetic evidence to argue for the existence of rodent emotionality, a model of human neuroticism. With the advent of molecular mapping techniques it has become possible to test this hypothesis. Here I review the progress that has been made, largely in animal genetic studies, demonstrating that a common set of genes act pleiotropically on measures of emotionality. More recently, evidence has emerged supporting the view that the same genes influence variation in both rodent and human phenotypes.     

The genetic basis of dyslexia

Dyslexia, a disorder of reading and spelling, is a heterogeneous neurological syndrome with a complex genetic and environmental aetiology. People with dyslexia differ in their individual profiles across a range of cognitive, physiological, and behavioural measures related to reading disability. Some or all of the subtypes of dyslexia might have partly or wholly distinct genetic causes. An understanding of the role of genetics in dyslexia could help to diagnose and treat susceptible children more effectively and rapidly than is currently possible and in ways that account for their individual disabilities. This knowledge will also give new insights into the neurobiology of reading and language cognition. Genetic linkage analysis has identified regions of the genome that might harbour inherited variants that cause reading disability. In particular, loci on chromosomes 6 and 18 have shown strong and replicable effects on reading abilities. These genomic regions contain tens or hundreds of candidate genes, and studies aimed at the identification of the specific causal genetic variants are underway.     

The genetic basis of cerebral palsy

Although prematurity and hypoxic–ischaemic injury are well‐recognized contributors to the pathogenesis of cerebral palsy (CP), as many as one‐third of children with CP may lack traditional risk factors. For many of these children, a genetic basis to their condition is suspected. Recent findings have implicated copy number variants and mutations in single genes in children with CP. Current studies are limited by relatively small patient numbers, the underlying genetic heterogeneity identified, and the paucity of validation studies that have been performed. However, several genes mapping to intersecting pathways controlling neurodevelopment and neuronal connectivity have been identified. Analogous to other neurodevelopmental disorders such as autism and intellectual disability, the genomic architecture of CP is likely to be highly complex. Although we are just beginning to understand genetic contributions to CP, new insights are anticipated to serve as a unique window into the neurobiology of CP and suggest new targets for intervention.     

The genetic basis of addictive disorders

Addictions are common, chronic, and relapsing diseases that develop through a multistep process. The impact of addictions on morbidity and mortality is high worldwide. Twin studies have shown that the heritability of addictions ranges from 0.39 (hallucinogens) to 0.72 (cocaine). Twin studies indicate that genes influence each stage from initiation to addiction, although the genetic determinants may differ. Addictions are by definition the result of gene × environment interaction. These disorders, which are in part volitional, in part inborn, and in part determined by environmental experience, pose the full range of medical, genetic, policy, and moral challenges. Gene discovery is being facilitated by a variety of powerful approaches, but is in its infancy. It is not surprising that the genes discovered so far act in a variety of ways: via altered metabolism of drug (the alcohol and nicotine metabolic gene variants), via altered function of a drug receptor (the nicotinic receptor, which may alter affinity for nicotine but as discussed may also alter circuitry of reward), and via general mechanisms of addiction (genes such as monoamine oxidase A and the serotonin transporter that modulate stress response, emotion, and behavioral control). Addiction medicine today benefits from genetic studies that buttress the case for a neurobiologic origin of addictive behavior, and some general information on familially transmitted propensity that can be used to guide prevention. A few well-validated, specific predictors such as OPRM1, ADH1B, ALDH2, CHRNA5, and CYP26 have been identified and can provide some specific guidance, for example, to understand alcohol-related flushing and upper GI cancer risk (ADH1B and AKLDH2), variation in nicotine metabolism (CYP26), and, potentially, naltrexone treatment response (OPRM1). However, the genetic predictors available are few in number and account for only a small portion of the genetic variance in liability, and have not been integrated into clinical nosology or care.     

The genetic basis of Parkinson's disease

Although the mechanisms underlying neurodegeneration in Parkinson's disease are not fully understood, considerable evidence suggests that genetic factors can influence susceptibility to the disease. In this article, we critically review this evidence and examine studies estimating patterns of inheritance. In a few families, Parkinson's disease is clearly inherited in a Mendelian fashion, and in some of these the disease causing genes have already been identified. Possible pathogenic mechanisms by which these genes cause Parkinson's disease are discussed. Further candidate genes and systematic efforts to identify genes influencing susceptibility to the disease in general are also summarised. The identification of such susceptibility genes will eventually enable us to more accurately classify this complex disease.     

The genetic basis of cerebral ventricular volume

Cerebral ventricular volume, assessed by computed tomography, is a genetically determined trait. In a series of 18 monozygotic and 18 dizygotic twins, heritability values ranged from 82% to 85% depending on the method of calculation.     

The history of ependymoma management

Introduction  

The ependymomas are relatively not a common tumor. However, most clinicians agree that the radical removal of the tumor is the most important prognostic factor.     

The genetic basis for psychiatric illness in man

Following the influential genetic studies of Heston and Kety, there has been growing acceptance of the role of genes in determining behaviour. It is now recognized that most types of behaviour, from normal variations in traits such as personality to complex psychiatric disorders, are influenced not only by environmental factors but also by multiple genes. While twin and adoption studies have been vital in demonstrating the heritability of behaviour, the focus is now on the identification of the genes involved using the molecular genetic strategies linkage analysis and allelic association. This article will discuss techniques that have been used in psychiatric genetics, and how they have advanced our understanding of complex behaviour.     

The genetic basis for the timing of human puberty

Puberty is a complex, coordinated biological process with multiple levels of regulation. Epidemiological observations suggest that the timing of pubertal events is a heritable trait, although environmental factors can modulate such genetic influence. The study of pathological states of early and late puberty has provided valuable insight into those genes that regulate gonadotrophin-releasing hormone (GnRH) activity. The development of pulsatile release of GnRH secretion mediated through kisspeptin-1 activation of G-protein coupled receptor-54 appears to be a central event at the onset and during progression of puberty. Stimulating and restraining influences (e.g. in the form of glutamatergic and GABAergic neuronal inputs) are likely to influence the timing of this process. The study of extreme variants of 'normality', such as constitutional delay of growth and puberty and early puberty, may lead to the recognition of additional genes and pathways that can modulate both the timing of pubertal onset and its tempo.     

The molecular genetic basis of the neuronal ceroid lipofuscinoses

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by the presence of autofluorescent lipopigment in neurons and other cell types. The childhood onset types display autosomal recessive inheritance. Naturally occurring animal NCLs have been described in many species including mouse, sheep and dog. In the last decade major advances have occurred in the molecular genetic analysis of the NCLs. Six disease gene loci have been mapped, and five disease genes have been isolated. Two of these encode lysosomal enzymes: CLN1 encodes palmitoyl-protein thioesterase (PPT), and CLN2 encodes tripeptidyl peptidase 1 (TPP1). The remaining three, CLN3, CLN5 and CLN8 encode putative membrane proteins of unknown function. The murine orthologue of CLN8 causes motor neuron degeneration (mnd), a mouse model of NCL. These advances have revolutionized diagnosis and classification, but a unified theory of pathogenesis and effective treatment remain elusive.     

The origin of schizophrenia: genetic thesis, epigenetic antithesis, and resolving synthesis.

Traditionally, it has been thought that schizophrenia results from the interaction of predisposing genes and hazardous environmental factors. In this article, the paradigm of "genes plus environment" is challenged, and a new interpretation is presented, in which the emphasis on DNA sequence variation is shared with epigenetic misregulation as a critical etiopathogenic factor. Partial epigenetic stability (metastability) of gene regulation is consistent with various nonmendelian irregularities of schizophrenia, such as the presence of clinically indistinguishable sporadic and familial cases, discordance of monozygotic twins, coincidence of peaks of susceptibility with major endocrine rearrangements, and fluctuating course of disease severity, among others. It is also suggested that stochastic epigenetic events might account for a substantial portion of phenotypic variance, which traditionally has been ascribed to environmental effects. This theoretic essay is constructed according to the principle of Hegelian dialectic reasoning (thesis-antithesis-synthesis), which serves the goal of showing that the best outcome of molecular genetic studies in schizophrenia (and perhaps other complex diseases) can be expected when components that effect chromatin structure and gene regulation are taken into account and investigated comprehensively.     

The genetic basis of non-syndromic intellectual disability: a review

Intellectual disability (ID), also referred to as mental retardation (MR), is frequently the result of genetic mutation. Where ID is present together with additional clinical symptoms or physical anomalies, there is often sufficient information available for the diagnosing physician to identify a known syndrome, which may then educe the identification of the causative defect. However, where co-morbid features are absent, narrowing down a specific gene can only be done by 'brute force' using the latest molecular genetic techniques. Here we attempt to provide a systematic review of genetic causes of cases of ID where no other symptoms or co-morbid features are present, or non-syndromic ID. We attempt to summarize commonalities between the genes and the molecular pathways of their encoded proteins. Since ID is a common feature of autism, and conversely autistic features are frequently present in individuals with ID, we also look at possible overlaps in genetic etiology with non-syndromic ID.     

Molecular basis of genetic neuropsychiatric disorders

The past decade has seen tremendous advances in our understanding of the molecular and genetic basis of many neuropsychiatric disorders. Although the genetic aberrations that lead to these syndromes have been identified in many cases, not much is known about specific gene products and their function. This article reviews the molecular basis of well-known neurogenetic disorders. The syndromes discussed here follow a Mendelian pattern of inheritance and are predominantly single-gene disorders; however, most childhood and adolescent psychiatric disorders are polygenic in nature. This genetic complexity and heterogeneity has made it difficult to identify the genes involved in their etiology. Identification of genetic and environmental risk factors involved in the etiology of complex disorders, such as autism, will help in the discovery of medications that can ameliorate the symptoms.     

Value of genetic and epigenetic testing as biomarkers of response to antidepressant treatment

Abstract

Major depressive disorder (MDD) is one of the most prevalent and disabling psychiatric disorders worldwide and therefore an important public health priority. The selection process of antidepressant treatment is primarily guided by trial and error, and the outcomes with current antidepressant strategies are disappointing. The biological background of the disease is heterogeneous with presumably multiple biological systems involved. With the aim to individualize antidepressant treatment, multiple candidate gene and a few genome-wide association studies have been performed, but so far with very limited success. To address the dynamic changes of depressive symptoms and their response to treatment, recent studies focus on epigenetic mechanisms, as these are modulated by environmental stimuli and adaptive to different stages of the disorder. In the present paper, after a brief summary of the most important results from pharmacogenetic studies in MDD, we comment on the current and potential future value of genetic testing as a biomarker of response to antidepressant treatment. The new and exciting field of epigenetic mechanisms in antidepressant drug treatment will be presented in the second part of this review.     

The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia

Specifying the complex genetic architecture of the "fuzzy" clinical phenotype of schizophrenia is an imposing problem. Utilizing metabolic, neurocognitive, and neurophysiological "intermediate" endophenotypic measures offers significant advantages from a statistical genetics standpoint. Endophenotypic measures are amenable to quantitative genetic analyses, conferring upon them a major methodological advantage compared with largely qualitative diagnoses using the Diagnostic and Statistical Manual of Mental Health, 4th Edition (DSM-IV). Endophenotypic deficits occur across the schizophrenia spectrum in schizophrenia patients, schizotypal patients, and clinically unaffected relatives of schizophrenia patients. Neurophysiological measures, such as P50 event-related suppression and the prepulse inhibition (PPI) of the startle response, are endophenotypes that can be conceptualized as being impaired because of a single genetic abnormality in the functional cascade of DNA to RNA to protein. The "endophenotype approach" is also being used to understand other medical disorders, such as colon cancer, hemochromatosis, and hypertension, where there is interplay between genetically conferred vulnerability and nongenetic stressors. The power and utility of utilizing endophenotypes to understand the genetics of schizophrenia is discussed in detail in this article.